A single gene
called cylE within the important bacterial pathogen Group B
Streptococcus (GBS), controls two factors that act
together as a “sword” and “shield” to
protect the bacteria from the killing effects of the immune
system’s white blood cells, according to researchers at
the University of California, San Diego (UCSD) School of Medicine.

GBS is the leading
cause of serious bacterial infections such as meningitis and
pneumonia in newborns and is increasingly recognized as a serious
pathogen in adult populations, including the elderly, pregnant
women and diabetics.

In studies with mice
and human blood samples, published in the online edition of
Proceedings of the National Academy of Sciences the
week of September 20, 2004, the UCSD scientists demonstrated
the protective roles of two cylE-encoded factors, one
that creates the unusual orange pigmentation of GBS, and another
that produces a toxin called hemolysin that kills immune system
cells as they surround and attack the bacteria. These findings
could lead to new therapeutic approaches that disarm the bacteria
and allow the immune system to do its work.

George
Liu, M.D., Ph.D., UCSD research fellow in pediatric infectious
diseases and lead author of the paper.

"A crucial part
of the body's defense against bacterial pathogens are white
blood cells known as neutrophils and macrophages, which are
able to engulf and kill most bacteria" said lead author
George Liu, M.D., Ph.D., a UCSD research fellow in pediatric
infectious diseases. "We predicted that the GBS bacteria
had a unique ability to avoid the killing by white blood cells."

This unique ability
turned out to include both the killing effects of the hemolysin
toxin, and previously unrecognized antioxidant properties of
the GBS orange pigment.

A major weapon that
white blood cells use to kill bacteria after engulfment is the
production of lethal oxidants similar to peroxide and bleach.
Interestingly, the cylE-dependent orange pigment belongs
to the family of carotenoids, similar to the compounds that
give color to vegetables such as tomatoes and carrots. The anitoxidant
properties of food carotenoids have long been touted for their
potential health benefits against aging, heart disease and cancer.

“Just as colorful
vegetables with antioxidants are touted for their ability to
protect us against aging or cancer, we discovered that the GBS
bacteria is pulling the same trick to protect itself against
our immune system,” said the study’s senior author,
Victor Nizet, M.D., associate professor, UCSD Division of Infectious
Diseases, and an attending physician at Children’s Hospital
San Diego.

A
single gene (cylE) of the newborn pathogen group B Streptococcus
(GBS) controls production of a hemolysin toxin that lyses
human cells and an orange pigment resembling carotene
that shields the bacterium from immune system killing.
Images show colonies of GBS bacteria grown on agar plates.

The UCSD experiments
confirmed the importance of the antioxidant role of the orange
pigment, as mutant GBS without the cylE gene was 10 to 10,000
times more susceptible to white blood cell oxidants than the
disease producing strain.

The new findings are
based on previous research by the UCSD group and others, that
showed cylE controls the production of hemolysin, as
well as the orange pigmentation of the gene. Removal of this
gene created a mutant strain of GBS that lacked the hemolysin
toxin and was plain white in color. When tested in animal models,
the mutant GBS strain was unable to produce serious infections.
In the current study, the scientists showed that the mutant
GBS strain was rapidly cleared from the bloodstream of experimental
animals and more easily killed by purified human and mouse white
blood cells.

The hemolysin toxin
was the “sword” that poked holes throughout white
blood cells, such that in many cases the GBS actually killed
the immune cell before it could kill the bacteria. However,
even when hemolysin production was inhibited, the GBS continued
to survive the white blood cell attack. In additional experiments,
the orange pigment was found to be the “shield”
that protected the bacteria. Combined, the toxin and orange
pigmentation made GBS a potent warrior against white blood cell
defenses and consequently a much more lethal pathogen.

“Recognizing
the importance of these two properties for GBS infection suggests
that novel drug treatments or vaccines that block the hemolysin
or disrupt pigment production may be quite effective. Essentially,
such therapies could make the GBS bacteria susceptible to elimination
by the normal immune system of the newborn infant," Nizet
said.

This work was supported
by the National Institutes of Health and a Howard Hughes Medical
Institute Fellowship to Liu, a Burroughs-Wellcome Career Award
to Doran, and an Edward J. Mallinckrodt, Jr. Scholar Award to
Nizet.